Functional Polymorphic Variants Of Methionine Metabolism Influence Neurotoxicity And Survival In Primary Central Nervous System Lymphoma (Pcnsl) Treated With High-Dose Methotrexate

8579 Background: Methotrexate (MTX) is the most efficient chemotherapeutic drug in primary central nervous system lymphoma (PCNSL); it directly interferes with methionine metabolism. Patients and Methods: Eight functional polymorphic variants influencing methionine metabolism were investigated in 65 PCNSL patients and were analyzed for their impact on the occurrence of confluent CNS white matter changes (WMC) (Pearson’s Chi-square test and multinominal regression analysis) and for their influence on survival (univariate Log Rank and multivariate COX regression analyses). Results: Twenty/65 (31%) patients developed WMC, which was significantly predicted by the genotype of methylenetetrahydrofolate reductase c.1298A>C (p.E429A; patients with WMC, AA/AC/CC: 0.80/0.10/0.10; patients without WMC: 0.40/0.47/0.13; nominal logistic regression: χ2=11.54; p=0.003). In addition, the transcobalamin 2 variant c.776C>G (p.P259R) influenced the occurrence of WMC (patients with WMC: 0.20/0.45/0.35; patients without WMC: 0.33/0.47/0.20; χ2=11.15; p=0.003) and survival (c.776CC: 105±7 months; c.776CG/GG: 69±9 months; Log Rank 4.79; p=0.029; Wald 4.15; p=0.042). Conclusions: The mutant c.776G-allele of the cobalamin transporter transcobalamin 2 leads to a reduced availability of methylcobalamin as cofactor for the synthesis of methionine and S-adenosylmethionine (SAM) from homocysteine. Since SAM is mandatory for DNA methylation and for CNS myelination, depletion of SAM may lead to WMC during MTX treatment. Further, the synthesis of methionine/SAM from homocysteine leads to a conversion of 5-methyltetrahydrofolate to 5,10-methylenetetrahydrofolate. We speculate that the effects of the transcobalamin 2 c.776C allele on tetrahydrofolate conversion and on SAM synthesis may be involved in the observed effect of this allele on occurrence of WMC and on survival. If confirmed in an independent patient sample, these observations may have an impact on MTX-based cancer treatment: Modification of methionine metabolism, e.g. by vitamine or amino acid supplementation, could have beneficial effects on both, treatment efficacy and neurotoxicity. No significant financial relationships to disclose.